Vascular cognitive impairment (VCI) is a heterogeneous entity that has been classically linked with ischemic disease. Furthermore, there is considerable evidence indicating that chronic cerebral hypoperfusion is an early feature of Alzheimer's disease (AD) and cardiovascular risk factors increase the incidence of both vascular cognitive impairment and AD. This has led many to speculate that chronic cerebral hypoperfusion could play important roles both in AD and VCI and could serve as a mechanistic link between these two entities. This proposal will address fundamental questions about the role of cerebral hypoperfusion in the development of age-related cognitive decline. Specifically, it will focus on its effects in the stability of synaptic connections, building up on preliminary observations we have made using time-lapse two-photon microscopy of neuronal structures in living mice. We have observed that dendritic spines the main sites of excitatory synaptic connections undergo remarkable destabilization in the presence of cerebral hypoperfusion in mouse models. This occurs in the absence of stroke, suggesting that hypoperfusion below the threshold for ischemia could be an underestimated mechanism of pathology. This proposal will systematically test mechanisms of neuronal circuit injury in cerebral hypoperfusion, examine their interactions with AD pathology and probe potential therapeutic strategies. Specifically, it will test the hypothesis that chronic cerebral hypoperfusion in the absence of ischemia induces synaptic destabilization and enhances the synaptotoxic effects of A[unreadable]-amyloid and neuroinflammation eventually leading to neurodegeneration. To test this hypothesis, we will use animal models of global and focal cerebral hypoperfusion, in vivo two-photon microscopy imaging of neuronal structures, amyloid plaques and microglia as well as histological and biochemical methods. In aim 1, we will further characterize the effects of chronic cerebral hypoperfusion on synaptic stability. In aim 2, we will examine the effects of chronic cerebral hypoperfusion on A[unreadable]-amyloid deposition and synaptotoxicity. In aim 3, we will investigate the role of neuroinflammation in hypoperfusion- induced synaptic disruption. Together, these studies will greatly advance our understanding of complex mechanisms through which CCH interacts with neurons, a-amyloid and microglia eventually leading to neuronal circuit injury and dementia. .